Cancer is the second leading cause of death in the United States, after heart disease (Boring, et al., CA Cancer J. Clin., 43:7, 1993), and it develops in one in three Americans. One of every four Americans dies of cancer. Cancer features uncontrolled cellular growth, which results either in local invasion of normal tissue or systemic spread (metastasis) of the abnormal growth. A particular type of cancer or a particular stage of cancer development may involve both elements.
Cancer is caused by inherited or acquired mutations in cancer genes, which have normal cellular functions and which induce or otherwise contribute to cancer once mutated or expressed at an abnormal level. Certain well-studied tumors carry several different independently mutated genes, including activated oncogenes and inactivated tumor suppressor genes. Each of these mutations appears to be responsible for imparting some of the traits that, in aggregate, represent the full neoplastic phenotype (Land et al., Science, 222:771, 1983; Ruley, Nature, 4:602, 1983; Hunter, Cell, 64:249, 1991).
Kinase enzymes have been shown to be important in intracellular signal transduction. One class of kinase enzymes involved in signal transduction is the Src-family of protein tyrosine kinases (PTK's), which includes, for example: Lck, Fyn(B), Fyn(T), Lyn, Src, Yes, Hck, Fgr and Blk (for review see: Bolen, J B, and Brugge, J S Annu. Rev. Immunol 1997, 15, 371). Gene disruption studies suggest that inhibition of some members of the Src family of kinases would potentially lead to therapeutic benefit. Src(−/−) mice have abnormalities in bone remodeling or osteopetrosis (Soriano, P. Cell 1991, 64, 693), suggesting that inhibition of the src kinase might be useful in diseases of bone resorption, such as osteoporosis. Lck(−/−) mice have defects in T cell maturation and activation (Anderson, S J et al. Adv. Immunol. 1994, 56, 151), suggesting that inhibition of the Lck kinase might be useful in diseases of T cell mediated inflammation. In addition, human patients have been identified with mutations effecting Lck kinase activity (Goldman, F D et al. J. Clin. Invest. 1998, 102, 421). These patients suffer from a severe combined immunodeficiency disorder (SCID).
The activated p21cdc42Hs-associated kinase (ACK1) gene encodes an intracellular, non-receptor tyrosine kinase that binds cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of p21cdc42, a Ras-like protein involved in cell growth (Manser et al., Nature 363(6427):364-367, 1993). This binding is mediated by a unique polypeptide of 47 amino acids C-terminal to an SH3 domain. ACK1 gene contains a tyrosine kinase domain and is reported to possess tyrosine kinase activity. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway.
ACK1 is a gene that is frequently amplified and overexpressed in primary human tumors (U.S. patent application No. 20030175763). ACK1 kinase activity is regulated in the context of cell attachment and detachment, and certain cancer cells depend on ACK1's kinase activity for adhesion, anchorage independent growth and survival. Down regulation of ACK1 kinase activity or ACK1 expression levels can result in reduced tumor growth in animal models.
In addition to ACK1, other kinases have been targets for oncolytic drugs. For example, WO 01/4750782, WO 97/02266A1, and WO 02/411882A2 each disclose EGF— or VEGF-inhibiting compounds that are 5-phenyl and 6-phenyl-substituted pyrrolo[2,3-d]pyrimidines, but only in combination with 4-phenylamino or 4-benzylamino substituents. WO 99/65909A1 describes 4-piperidin-1-yl-substituted pyrrolo[2,3-d]pyrimidines that inhibit Janus Kinase 3 (“JAK3”). WO 02/096909, WO 02/00661A1, and U.S. Pat. Nos. 6,610,847B2 and 6,627,754B2 also disclose JAK3-inhibiting compounds in which the 5- and 6-positions on the pyrrolopyrimidine ring can be aryl or alkynyl; and the 4-position substituent can be of the type:
where R4 can be hydrogen; y can be 0, 1, or 2; and R5 is, inter alia, a substituted (C2-C9)heterocycloalkyl ring (see, e.g., the '909 and '807 publications).
Nevertheless, there remains a need for new cancer treatments. In particular, there is an especially acute need for new cancer treatments that exploit unique biochemical targets such as ACK1 and LCK. The present invention meets these and other needs.